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The Role of Intestinal Flora in Autism and Nutritional Approaches

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The Role of Intestinal Flora in Autism and Nutritional Approaches Demiroglu Science University Florence Nightingale Journal of Transplantation2020;5(1-2):61-69 doi: 10.5606/dsufnjt.2020.017 The role of intestinal flora in autism and nutritional approaches Aslı Melike Ekmekçi1, Oytun Erbaş1,2 1Institute of Experimental Medicine, Gebze-Kocaeli, Turkey 2Department of Physiology, Medical Faculty of Demiroğlu Bilim University, Istanbul, Turkey ABSTRACT Autism spectrum disorder (ASD) is a social behavior disorder and awareness on ASD has been increasing nowadays. Social deficiencies and repetitive movements constitute the symptoms of ASD occurring in childhood. As there is no biological marker in autism, parental and clinician approaches are based on diagnosis. Genetic and environmental factors play a role in autism, and its prevalence has been increasing in recent years. The process and amount of exposure to environmental factors create differences in the cause of autism. Although it is unclear yet whether autism is a cause or result, impaired intestinal flora is among the symptoms of autism. Factors such as nutrition approaches and perinatal factors have been thought to play a role in intestinal flora dysbiosis. Metabolites that cross the blood-brain barrier in the intestinal flora dysbiosis can cause morphological changes in the hippocampus in the brain. Various dietary approaches and fecal microbiota transplantation have become candidates for autism treatment methods to improve the deteriorated flora. In this review, we discuss the effects of therapeutic nutritional approaches and fecal transplantation by examining the relationship between ASD and intestinal flora. Keywords: Autism spectrum disorder, intestinal flora, nutrition Autism spectrum disorder (ASD) is a behavioral are heavy metals, antibiotics and chemical disorder characterized by language and social toxic substances. Other causes include diet, deficiencies that occur in childhood. Repetitive infections (Morbilli/measles, human herpesvirus behaviors, obsessions, and communication 6/HHV6, cytomegalovirus/CMV, Streptococci, difficulties are observed in autism. Autism was Clostridia, Borrelia, and Candida spp.), mode first described in the literature by the American of delivery, oxygen deficiency during delivery psychiatrist Leo Kanner as “early childhood and after delivery, and differences in cerebral schizophrenia” in 1943.[1] According to the blood supply. Autism is seen in children who National Health Statistics Report published in the cannot cope with environmental problems United States, the prevalence of autism, which due to their genetic tendencies, as a result was 1:86 in 2007, increased to 1:50 in 2012.[2] of a series of mechanisms. Therefore, these Factors such as increased awareness of physicians environmental factors in autism, the intestinal and parents, differences in diagnostic criteria, flora (microbiota) is differentiated. Differentiated widespread use of screening scales and keeping microbiota lead to gastrointestinal symptoms in accurate data are effective.[3] individuals with autism. Genetic and environmental factors play a role In this review, we discuss the effects of in the pathogenesis of ASD. Although single- microbiota, the effects of microbiota on autism, gene polymorphisms are effective in autism, nutritional approaches, and the effects of fecal autism does not occur without environmental microbiota transplantation (FMT) on autism as an factors. Among the major causes of autism alternative treatment method.[1,4] Correspondence: Aslı Melike Ekmekçi. Deneysel Tıp Enstitüsü, 41470 Gebze-Kocaeli, Türkiye. e-mail: [email protected] Cite this article as: Ekmekçi AM, Erbaş O. The role of intestinal flora in autism and nutritional approaches. D J Tx Sci 2020;5(1-2):61-69. 62 D J Tx Sci INTESTINAL FLORA (MICROBIOTA) addition, almost all children with autism do not have a normal intestinal flora.[1,11,12] In a meta- The intestinal microbiota contains about analysis of 144 studies, constipation was found 3 million genes, or 150 times more genes to be in 4.3 to 45.5%, diarrhea in 2.3 to 75.6%, [5] than the human genome. Colonization in the and more than one symptom in 4.2 to 96.8%.[13] human body first begins with exposure to the mother's vaginal microbiota during delivery. The Abnormal intestinal functions in autism affect intestinal microbiota of infants delivered vaginally the brain due to increased permeability. The gut- is similar to the vaginal microbiota of their brain axis, which is a communication pathway mothers dominated by Lactobacillus, Prevotella or between the gut and the brain, has been accepted Sneathia spp., the intestinal microbiota of infants as a two-way communication system. The gut- delivered by cesarean section is Staphylococcus, brain axis plays a role in the pathogenesis of Corynebacterium and Propionibacterium spp., ASD. Intestinal microbiota affects brain function and observed to be similar to the skin microbiota through the neuro-endocrine, neuro-immune, of mothers.[6] autonomic nervous systems, and toxin production of the microbiota.[14] Stool samples that obtained There are two dominant types of bacteria from children with ASD revealed higher levels of in the human microbiota: Bacteroidetes and Clostridium histolyticum compared to samples Firmicutes filum. Proteobacteria, Actinobacteria, from healthy unrelated children. In addition, Fusobacteria and Verrucomicrobia phylum are intestinal dysbiosis has occurred in children less common.[7] The microbiome in the first with autism.[15] The main factor underlying the meconium of mice is not sterile, indicating that relationship between ASD and the intestine is the microbiome colonizes the infant intestines the increased permeability of the intestinal tract before birth.[8] Subsequent interactions with of individuals with ASD, and this is referred nutrition and the environment result in increased to as leaky gut[16] According to the leaky gut intestinal flora diversity. Microbial diversity differs hypothesis, the permeability of the mucosal among individuals in terms of diet, hygiene, barrier increased with reduced tight-junction social behavior, vaccination and genetic factors.[6] activity. Since the function of intestinal cells is Studies have revealed significantly more clostridia impaired, vitamins, minerals and other nutrients and ruminococcus in the stool of the autistic related to carrier proteins cannot pass into the group with gastrointestinal (GI) symptoms.[9] blood sufficiently. Therefore, related symptoms Hippocampal neurodevelopment was altered in of inadequacy occur. It has been suggested that two groups of mice whose microbiota was altered gliadamorphine and casomorphine, which are with germ-free antibiotics and consequently spatial partial digestive products of harmful substances and object recognition was impaired.[10] produced by microorganisms such as gliadin and casein, cross the intestinal barrier and affect the AUTISM - MICROBIOTA functions of the central nervous system (CNS) by passing to the blood and then to the brain. These A potential connection between microbiota opioid proteins cause behavioral changes in the and ASD has been suggested over two decades brain and gut, constipation, bloating and diarrhea. ago. Recent studies suggest that autism is a Morphine poisoning might be the most likely disease scene that begins in the gastrointestinal reason why children with autism are resistant system and shows results in the brain. First, oral to pain.[17,18] Although it is not clear whether the vancomycin therapy provides a short-term benefit impaired microbiota is the cause or the result of in a small group of children with ASD, and later, autism yet, metabolites have crossed the blood- intestinal bacteria research in children with ASD brain barrier and formed the gut brain axis as a revealed differences compared to the control result of the increased permeable flora. group. Since then, numerous studies from various cohorts have reported that the microbiome AUTISM - MICROBIOTA - ANIMAL profiles of ASD individuals, particularly those with comorbid gastrointestinal dysfunction, differ from MODELS control groups. More than half of the children Epidemiological studies have identified with autism have gastrointestinal problems. In exposure to infection in the neonatal period as a The role of intestinal flora in autism and nutritional approaches 63 risk factor for a number of neurological disorders offspring. These factors cross the placenta, affect such as autism and schizophrenia. Immunogen the development of the neuronal circuits of the activation (MIA) is performed with propionic acid offspring, impair the behavioral phenotype and (PPA), valproic acid (VPA), lipopolysaccharide increase the risk of developing ASD.[26] A study (LPS) or polycytidylic acid: (i.e. poly(I:C)) to create found that mothers whose pre-pregnancy weight a model of autism in mice. Autism-like behaviors, is over 90 kg are more likely to develop autistic including impaired communication, were observed children. Therefore, a clear relationship can be particularly in male rats by administering PPA established between obesity during pregnancy mg/kg for three days or giving LPS 100 μg/kg and ASD formation in offspring. Factors such intraperitoneally to create a rodent model with as the mother's age, diet, mode of delivery and autistic characteristics. In additional method, environment and stress have been evaluated autism symptoms occur when VPA is dissolved in as perinatal factors in autism by affecting the saline by intraperitoneal injection and
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